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pklittle wrote:will some of us get angioplasty and others not but think they did for sake of testing the "placebo" effect?

pklittle - I believe Dr. S is saying below that there won't be a placebo group. If the patients are paying for treatment, I wouldn't imagine there could be a placebo group anyway. Patients or insurance can't be expected to pay for a sham treatment.

drsclafani wrote:

1eye wrote:

drsclafani wrote:only by comparing the two groups can we tell how much of the effects was actually due to the treatment.

sometimes the research means well but is not empathic. But science is not empathic, it is raw, unbiased and objective. We need it to sort this out.

i feel your anger and frustration. It is clear to me that you mistrust the medical sciences. when you are on the wrong side of bias, it is infuriating. But who is to say whose bias will ultimately be correct. That is the goal of a trial

I can't agree. I could tell I was on placebo. Any SPMS patient knows when nothing has changed. They'll know, and everybody will chalk it up to science.

Intention to treat? With a well-known proven-impotent psychological bias that's equivalent to no treatment at all? You think this is blinded? It is unethical voodoo of the worst kind. If someone thinks patient bias will be toward treatment, and their bias cures or treats anything, or improves anything, well, I know some cancer patients. Would you like to try convincing *them* that their next chemo course will work if they just believe hard enough, and clap their hands three times? And you'll leave things that way for two years, right?

I know science can be harsh. But to dismount the riders of that horse requires ethics, not lack of science. It requires the spirit and not just the letter of 'do no harm.' Harm can come by inaction as well as action.

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Hi doctor.Ok here it is. When your neck starts to hurt again you rexperience problems. Even though I think we missed something else to begin with (inever got fully warm hands and feet) I deffinately had good improvements over the first month. Now my neck is starting to hurt again and when it does symptoms worse. Look you can;t fake improved walking and I had it but when my neck hurts everything worse. Restenosis probably plus if I remember correctly there were issues seeing azygous and you now have better method of viewing. Still think stents are in my future. Waiting with baited breath to be rechecked and retreated. Barbara
Oh listen there is still wax and wane sometimes no pain walked 150ft no hands two days ago. yesterday neck killed heat bothered me barely waddled touching walls .

Dr. Sclafani,
First I want to THANK YOU SO MUCH for your absolute kindness, humor and dedication to all MS patients - YOU DO ROCK!!!!!! as does HOLLY!!
I am quite new to this forum and wonder if you can help. My daughter suffered brain trauma and outer hematoma in Oct 05 (among other things) from cab running lights and was diagnosed with MS a year later with no prior symptoms.
Would you know if its safe to have CCSVI as we are thinking of going to Poland in early June? We are also on your waiting list but getting desperate.
She is also about to start Tysabri this week and worried that we should see how that goes first.......
(Name is not really Drury)

drsclafani wrote:I think it will be difficult to do a true randomized prospective double blinded study because of ethical and safety issues. Lets just keep thinking collectively and come up with the best COMPROMISE. It has to be something that neurologists will accept unless we want interventional radiologists to become neurologists

Okay, to summarize some of the ideas that have been tossed around:

Goosey-Gander as much as possible by explicitly mimicking protocols of drug trials.

Toss out any thought of sham treatment as unethical because of the risk of harm to those not being treated.

Let subjects be their own controls by comparing medical history before and after treatment.

Stagger treatment since everyone cannot be treated at once anyway with those untreated serving as controls for those who have been treated in each stage of the study.

[The limitation of both the above approaches is that subjects know they have not been treated so there is no placebo effect.]

Limit end points to a few, important measures such as fatigue and relapses which require hospitalization and/or treatment, pre- and post- procedure, and start measuring and reporting on them in quarterly intervals with the idea of reporting some results sooner rather than later, but doing long term study with continuously updated statistics. (Hard to shoot a moving target.)

Blind those doing the assessments as far as who has and hasn't had treatment.

Do unblinded comparative treatment rather than blinded placebo-controlled treatment. What scientific validity I might lose from comparison of open label treatments, may be offset by the greater knowledge gained about the efficacy of the treatments being compared.

Is it possible to take this much further and get a very large group to participate through a registry in comparing open label treatments, and a limited set of objective rather than subjective end points? (When you can't overwhelm them with scientific validity, flood them with data?)

I know there are many other ideas that have been tossed out. These are the ones that stuck.

drsclafani wrote:only by comparing the two groups can we tell how much of the effects was actually due to the treatment.

sometimes the research means well but is not empathic. But science is not empathic, it is raw, unbiased and objective. We need it to sort this out.

i feel your anger and frustration. It is clear to me that you mistrust the medical sciences. when you are on the wrong side of bias, it is infuriating. But who is to say whose bias will ultimately be correct. That is the goal of a trial

The FDA is not alone in pushing for placebo controls. For example, a recent textbook on clinical drug trials advocates using them because "if a new drug has only been compared to an active control (without a placebo-controlled trial), this is not a convincing proof of efficacy (even if equivalence can be demonstrated)."37 Without justification, such statements confer on placebo control a stature that ranks it with double blinding and randomization as a hallmark of good science.

The randomized, controlled trial is well recognized as the most desirable type of study in which to evaluate a new treatment. This recognition acknowledges the essential role of comparison and the importance of randomization in enhancing the comparability of two or more treatment groups. Using a placebo for comparison controls for the psychological effects of receiving some treatment and also permits blinding. No scientific principle, however, requires the comparison in a trial to involve a placebo instead of, or in addition to, an active treatment. Why, then, are placebo controls considered important? Three arguments have been advanced, none of which withstands scrutiny.

Establishing a Reference Point

By allowing the investigator to determine whether a new treatment is better than nothing (beyond the psychological benefits of treatment), a placebo control offers a clear benchmark. After all, even if a new treatment is worse than an existing one, it may still be "effective" in that it is better than no treatment. On the other hand, as Hill pointed out in 1963, the essential medical question at issue is how the new treatment compares with the old one, not whether the new treatment is better than nothing1.

Avoiding Difficult Decisions about Comparison Treatments

Determining whether one treatment is better than another is not always a straightforward matter. Beyond the question of efficacy, one can and should take into account unintended effects, interactions, costs, routes of administration, and other factors. Thus, it may appear simplistic to demand that the best proven treatment be chosen as the standard for comparison, if "best proven" refers only to efficacy. For some patients there may be advantages to a treatment that is inferior to a current standard with regard to efficacy but better with respect to cost or quality of life. For example, the adverse effects of some accepted treatments might offset the therapeutic benefits for some patients sufficiently that a placebo control would be ethically justified. This reasoning involves a complex decision that should be defended in submitted research proposals and published reports. It is not justifiable, however, to assign placebo controls simply to avoid the complex decision of which treatment should be used as a standard. Investigators are ethically obliged to make such decisions.

Bolstering Statistical Significance

One FDA scientist contends that placebo-controlled trials are superior to studies using an active treatment as the control because it is much easier to demonstrate a statistically significant effect in the former case36. The FDA relies heavily on statistical significance in judging the efficacy of new drugs36. Despite its popularity, however, this tool is not a good one for measuring efficacy38,39,40,41,42. The significance of an association depends on two characteristics -- the strength of the association and its statistical variability. A weak effect can be "significant" if there is little statistical variability in its measurement, whereas a strong effect may not be "significant" if there is substantial variability in its measurement. Of the two characteristics, only the strength of the effect should be fundamental to the decision about approval of the drug. Ideally, statistical variability should be reduced nearly to zero when the magnitude of a drug effect is assessed, so that random error does not influence the assessment.

Unfortunately, the main way to reduce statistical variability is to conduct large studies, which are expensive. Statistical significance, on the other hand, can be obtained even in small studies, if the effect estimate is strong enough. When a placebo control is used instead of an effective treatment, the effect of a new drug appears large and may be statistically significant even in a small study. The scientific benefit, however, is illusory. Because the study is small, the measurement of the effect is subject to considerable statistical error. Thus, the actual size of the effect, even when a new drug is compared with placebo, remains obscure, and the study does not address the question of the effectiveness of the new treatment as compared with currently accepted treatments.

The small placebo-controlled studies fostered by the FDA benefit drug companies, which can more easily obtain approval of an inferior drug by comparing it with placebo than they can by testing it against a serious competitor. Smaller studies are also cheaper. Unfortunately, the costs saved by the drug company are borne by patients, who receive placebos instead of effective treatments, and by the public at large, which is supplied with a drug of undetermined efficacy.

There is no sound scientific basis for these arguments on behalf of placebo controls. Furthermore, regardless of any apparent merit these arguments have, scientific considerations should not take precedence over ethical ones, even if the use of active controls requires more difficult decisions about study design, more costly studies, and more complicated analyses.

pklittle wrote:Dr SclafaniWhen you are "back in the saddle", and you start picking away at the list that you have of those of us wanting you to treat them.... will some of us get angioplasty and others not but think they did for sake of testing the "placebo" effect?Sorry for the long run on sentence... Pam

pam
we are going to do an open label safety study, not a randomized prospective blinded treatment trial. A randomized trial will require funding and a multicenter organization that is not in place now. It is my understanding that most studies being developed are of the safety, feasibility type
The goal will be to assure safety and get a sense of effectiveness in treatment.

As i said, i cant even figure out how to take a minimally invasive procedure that can be done under local anesthesia and put patients under general anesthesia so that they cannot tell whether they are treated or not. Hard to imagine an IRB committee agreeing to that one. I find it inhumane at this point.

So all patient in my study will be enrolled and be treated if findings warrant. No patients enrolled will not be treated unless i can find nothing to treat.

What the trial does is protect patients. I place my treatments under the watchful eyes of an IRB. I will be required to periodically summarize to them my work, reporting complications and adverse outcomes. If the procedural outcomes are too risky or harmful to patients, the IRB can stop the study. If this safety trial and others shows overwhelming data supporting treatment, things could well never get to a randomized trial

Drury wrote:Dr. Sclafani, First I want to THANK YOU SO MUCH for your absolute kindness, humor and dedication to all MS patients - YOU DO ROCK!!!!!! as does HOLLY!!I am quite new to this forum and wonder if you can help. My daughter suffered brain trauma and outer hematoma in Oct 05 (among other things) from cab running lights and was diagnosed with MS a year later with no prior symptoms. Would you know if its safe to have CCSVI as we are thinking of going to Poland in early June? We are also on your waiting list but getting desperate.She is also about to start Tysabri this week and worried that we should see how that goes first.......(Name is not really Drury)

I am so sorry that i must wait IRB approval before continuing treatments.

I can see no reason why a head injury five years ago would make things unsafe for angioplasty of the veins.

My suggestion is that you speak to several people who have gone to Poland. Who provides their after care? Do they return to Poland ?

Something thats also bothered me is that the bnac (buffalo) study hasn't found ccsvi in the same high numbers zamboni and others have.. I thought it would be interesting to study the ms lesions of those found to have ccsvi vs. those who did not.. The term venocentric has been used when describing lesions.. so do we need Tesla 7 mri's to study this?

Dr Haacke says that susceptibility weighted imaging (SWI) can be done even on the lowly 1.5 T magnets

it will be interesting to see if Dr. Zivadinov's second go around with US shows an increased number of MS patients as his and his technologists experience improves

this seems really important, as his low correlation numbers are constantly used as ammo in the FUD being spread against CCSVI

The FDA is not alone in pushing for placebo controls. For example, a recent textbook on clinical drug trials advocates using them because "if a new drug has only been compared to an active control (without a placebo-controlled trial), this is not a convincing proof of efficacy (even if equivalence can be demonstrated)."37 Without justification, such statements confer on placebo control a stature that ranks it with double blinding and randomization as a hallmark of good science.

The randomized, controlled trial is well recognized as the most desirable type of study in which to evaluate a new treatment. This recognition acknowledges the essential role of comparison and the importance of randomization in enhancing the comparability of two or more treatment groups. Using a placebo for comparison controls for the psychological effects of receiving some treatment and also permits blinding. No scientific principle, however, requires the comparison in a trial to involve a placebo instead of, or in addition to, an active treatment.

Why, then, are placebo controls considered important? Three arguments have been advanced, none of which withstands scrutiny.

Establishing a Reference Point On the other hand, as Hill pointed out in 1963, the essential medical question at issue is how the new treatment compares with the old one, not whether the new treatment is better than nothing1.

Avoiding Difficult Decisions about Comparison Treatments

It is not justifiable, however, to assign placebo controls simply to avoid the complex decision of which treatment should be used as a standard. Investigators are ethically obliged to make such decisions.

Bolstering Statistical Significance[/b]

When a placebo control is used instead of an effective treatment, the effect of a new drug appears large and may be statistically significant even in a small study. The scientific benefit, however, is illusory.

The small placebo-controlled studies fostered by the FDA benefit drug companies, which can more easily obtain approval of an inferior drug by comparing it with placebo than they can by testing it against a serious competitor. Smaller studies are also cheaper.

There is no sound scientific basis for these arguments on behalf of placebo controls.

unfortunately, there is no alternative to angioplasty and or angioplasty with stenting for CCSVI. Thus the control in this circumstance is NO TREATMENT. One cannot compare Liberation to drug therapy. Afterall, we have been quite vocal about the fact that we are not treating MS.

Furthermore, this is not a drug trial, but a minimally invasive treatment procedure. Thus placebo is almost impossible and unlikely to be considered ethical. The first question that must be answered is safety. The second question is effectiveness. The other questions mentioned in your email, cost, etc are really moot if the treatment has no lasting consequences. When evaluating a treatment with no other options, one should really compare the treatment to NO treatment. How one proves that treatment is better than no treatment requires controlling for placebo effect? We could use patient controls but there are holes in that. For example, dr Zamboni compared patients to their own historical control. He documented that liberati had less exacerbations and new plaques on MRI. Problem is that in the natural history of MS, exacerbations decrease in frequency as the disease worsens.

So we must continue the search for rational approach to determing the role of Liberation.As Rothman and Michels say

Furthermore, regardless of any apparent merit these arguments have, scientific considerations should not take precedence over ethical ones, even if the use of active controls requires more difficult decisions about study design, more costly studies, and more complicated analyses.

Something thats also bothered me is that the bnac (buffalo) study hasn't found ccsvi in the same high numbers zamboni and others have.. I thought it would be interesting to study the ms lesions of those found to have ccsvi vs. those who did not.. The term venocentric has been used when describing lesions.. so do we need Tesla 7 mri's to study this?

Dr Haacke says that susceptibility weighted imaging (SWI) can be done even on the lowly 1.5 T magnets

it will be interesting to see if Dr. Zivadinov's second go around with US shows an increased number of MS patients as his and his technologists experience improves

this seems really important, as his low correlation numbers are constantly used as ammo in the FUD being spread against CCSVI

As more safety trials are initiated, i suspect that catheter venography, the gold standard, will show that patients with MS have a high association with CCSVI. Zamboni is the only published results but most others doing venography also see a very high association. I didnt have one patient who did not have obviously stiff, noncompliant central IJV and/or bizarre valvular structure.

drsclafani wrote:unfortunately, there is no alternative to angioplasty and or angioplasty with stenting for CCSVI. Thus the control in this circumstance is NO TREATMENT. One cannot compare Liberation to drug therapy. Afterall, we have been quite vocal about the fact that we are not treating MS.

Can't you compare venoplasty PLUS drug treatment to just drug treatment? We could have both groups be on an accepted treatment, right? So the treated group would also be on one of the accepted therapies as well as undergo venoplasty.

Furthermore, this is not a drug trial, but a minimally invasive treatment procedure. Thus placebo is almost impossible and unlikely to be considered ethical.

This can't be the first time that this problem was encountered though, is it with a minimally invasive procedure? How was it handled before?

At least in this situation, we can eliminate SUBJECTIVE valuations of improvements by not only blinding researchers but also by conducting objective neuro assessments, i.e., EDSS, MRI, evoked potential, basic neuro exams before and periodically afterwards, then compare them with the group only receiving standard treatment.

drsclafani wrote:I think it will be difficult to do a true randomized prospective double blinded study because of ethical and safety issues. Lets just keep thinking collectively and come up with the best COMPROMISE. It has to be something that neurologists will accept unless we want interventional radiologists to become neurologists

Okay, to summarize some of the ideas that have been tossed around:

Goosey-Gander as much as possible by explicitly mimicking protocols of drug trials.

Toss out any thought of sham treatment as unethical because of the risk of harm to those not being treated.

Let subjects be their own controls by comparing medical history before and after treatment.

Stagger treatment since everyone cannot be treated at once anyway with those untreated serving as controls for those who have been treated in each stage of the study.

[The limitation of both the above approaches is that subjects know they have not been treated so there is no placebo effect.]

Limit end points to a few, important measures such as fatigue and relapses which require hospitalization and/or treatment, pre- and post- procedure, and start measuring and reporting on them in quarterly intervals with the idea of reporting some results sooner rather than later, but doing long term study with continuously updated statistics. (Hard to shoot a moving target.)

Blind those doing the assessments as far as who has and hasn't had treatment.

Do unblinded comparative treatment rather than blinded placebo-controlled treatment. What scientific validity I might lose from comparison of open label treatments, may be offset by the greater knowledge gained about the efficacy of the treatments being compared.

Is it possible to take this much further and get a very large group to participate through a registry in comparing open label treatments, and a limited set of objective rather than subjective end points? (When you can't overwhelm them with scientific validity, flood them with data?)

I know there are many other ideas that have been tossed out. These are the ones that stuck.

at some point we can tackle whether treating CCSVI is preferable to treating MS with all the pharaceuticals. That will be fun and not require placebo.

Of course, no one would advocate for that right now. until we prove that there are positive effects of liberation that are at least short term durable.

agreed, we likely cannot do a placebo control for ethical reasons. That leaves safety and efficacy studies that are so overwhelming that placebo cannot be seriously considered unless we also implicate mass hysteria among doctors and patients.

drsclafani wrote:it will be interesting to see if Dr. Zivadinov's second go around with US shows an increased number of MS patients as his and his technologists experience improves.

this seems really important, as his low correlation numbers are constantly used as ammo in the FUD being spread against CCSVI

I had a dream that we all got together and chipped in a few dollars to have you do catheter venography on a random group of Dr. Z's CCSVI-negative patients at the new Sclafani Center for Neuro Vascular Research and Internet Cafe in Brooklyn, NY. With your cape and "S" on your chest, you ended all the FUD that is being generated when you found that 100% were actually positive for CCSVI.

** BNAC found that approximately 80% of those with Relapsing-Remitting MS were CCSVI positive on u/s which is comparable to the Ferrara number. Ferrara's 100% figure is the result of catheter venography, not u/s.

** BNAC's healthy controls included first order family members so it is not unexpected that some may have CCSVI without having been dx'd with MS.

** BNAC included pediatric and CIS subjects something that was not done in Ferrara.

** Most importantly, he points out that 56%/62% is a BIG numbers in the grand scheme of things, even if it isn't 100%.

** Although Italian Dr. Z doesn't mention it, NY Dr. Z said he expects different numbers in the next 500 because they now have the proper u/s equipment.

Still I think testing some of those who were said not have CCSVI is the only way to address the FUD around this study.

eric593 wrote:Can't you compare venoplasty PLUS drug treatment to just drug treatment? We could have both groups be on an accepted treatment, right? So the treated group would also be on one of the accepted therapies as well as undergo venoplasty.

we could, but how do we know whether the effects were due to placebo effect?as i said, also, we have argued very loud for liberation not treating MS. now you want to use a drug plus liberation against drug without liberation......sounds like dr zamboni's trial

Furthermore, this is not a drug trial, but a minimally invasive treatment procedure. Thus placebo is almost impossible and unlikely to be considered ethical.

This can't be the first time that this problem was encountered though, is it with a minimally invasive procedure? How was it handled before?

worth exploring

At least in this situation, we can eliminate SUBJECTIVE valuations of improvements by not only blinding researchers but also by conducting objective neuro assessments, i.e., EDSS, MRI, evoked potential, basic neuro exams before and periodically afterwards, then compare them with the group only receiving standard treatment.

Couldn't we at least remove the subjective valuation component?

some of the most profound effects are very subjective improvements in quality of life. How does one measure improved tolerance to hot weather, pain, mental confusion, depression?
I do not want to take these important benefits out of the value of liberation

drsclafani wrote:How does one measure improved tolerance to hot weather

Do a quick neurological exam, crank the heat in the room, wait twenty minutes, do the neurological exam again? Or have them do a crossword puzzle, stick them in a hot room for an hour, then do a crossword puzzle again? Hypothesis being that liberated patients would maintain their abilities to do the puzzle, measured in time and errors, while nonliberated would experience a drop-off in abilities.

For depression, there is the Beck Depression inventory.

I'd bet a neuropsychologist has a test for mental confusion.

Even small improvements could be enough to be statistically significant.

"However, the truth in science ultimately emerges, although sometimes it takes a very long time," Arthur Silverstein, Autoimmunity: A History of the Early Struggle for Recognition

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